Classical Pavlovian conditioning has a major role in the development and persistence of drug addiction. Consistent with this view, exposure of drug-abstained subjects to drug-associated cues precipitates relapse which is a major problem in the management of drug addiction. To avert the recurrence of relapse it is necessary to develop pharmacotherapies and behavioral practices that will ultimately result in resistance to drug-associated cues and drug priming. The conditioned place preference (CPP) paradigm is an exemplar of classical Pavlovian conditioning which involves associative learning and memory processes. CPP has been successfully used in animal models to investigate several elements of addictive behavior. These include habit learning, the development of conditioned response to drug-associated cues, as well as the extinction and reinstatement of the conditioned behavior. The overarching goal of this application is to investigate how manipulations of associative learning and memory processes control drug-seeking behavior as modeled in cocaine-induced place preference. The hypothesis to be tested is that nitric oxide (NO) and its downstream signaling molecules cGMP and cAMP are involved in associative learning and memory processes relevant to drug addiction. Using the mouse model, the role of NO signaling in extinction learning of cocaine place preference will be investigated. The first specific aim will test the hypothesis that increases in brain NO, cGMP and cAMP facilitate consolidation of extinction learning and prevent the reinstatement of conditioned behavior. The effects of NO donors, and selective phosphodiesterase (PDE) inhibitors, which inhibit cGMP and cAMP degradation, on extinction of cocaine CPP will be investigated (Year 01). The second aim will test the hypothesis that inhibition of nNOS and soluble guanylate cyclase (sGC) impairs extinction of cocaine CPP. The effect of nNOS and sGC inhibitors on extinction of cocaine CPP will be investigated (Year 02). This aim will establish if resistance to extinction, a problem that underlies the management of drug addiction, is dependent on deficits in NO signaling pathway. In keeping with a translational research approach, all pharmacological treatments will be administered after the establishment of cocaine-induced conditioned behavior in order to increase the relevance of our findings to the clinical setting. Overall, results of these studies will reveal: a) potential new pharmacotherapies for the extinction of drug-induced conditioned behavior, and b) the role of NO signaling in learning and memory processes relevant to addictive behavior.